Non-lymphoid structural cells of tissues are recipients of inflammatory signals from immune cells, but they also make inflammatory products that can affect the migration, localization, and activity of immune cells in the tissues. Together this contributes to the pathologic changes that are seen in many diseases. In particular, epithelial cells, fibroblasts, and smooth muscle cells can become deregulated and contribute to fibrosis and tissue remodeling that impair normal organ functioning. This is often seen in chronic forms of autoimmunity or severe inflammatory diseases such as asthma or atopic dermatitis with overexuberant responses to allergens. TNF, that is the target of many FDA approved drugs for diseases such as psoriasis and rheumatoid arthritis, contributes to these processes as its primary receptor TNFR1 is expressed on most non-lymphoid structural cells. Similarly, a number of other TNF family receptors have now been found expressed on structural cells and their signals can bring about changes that are characteristic of disease. This includes driving the production of extracellular matrix proteins such as collagen, fibronectin, and fibrillin, that are products of fibroblasts and epithelial cells, and can restrict cellular spaces within tissues. It also includes making inflammatory cytokines such as TSLP and IL-33, or various chemokines, that act on many immune cell types, such as eosinophils, neutrophils, and macrophages, to promote their movement into tissues and drive their functional responses. Further activities include causing the differentiation of fibroblasts into smooth muscle-like cells, and also inducing an increase in the mass of smooth muscle cells and their contractility. The lab is currently focusing on how LIGHT, TL1A, and TWEAK promote responses in structural cells linked to diseases of the lung and skin, including asthma, idiopathic pulmonary fibrosis, systemic sclerosis, atopic dermatitis and psoriasis. Understanding how these TNF family proteins act, and how their combined signals drive tissue pathology, is likely to lead to new therapeutic approaches for limiting and resolving these types of disease.
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